Valsartan, the generic name for N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-L-valine (denoted as formula I below) is a well known nonpeptide angiotensin II AT1-receptor antagonist and is on the market as Diovan or Tareg for the treatment of hypertension.
According to U.S. Pat. No. 5,399,578 and Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 1, pp. 29-34, 1994, valsartan is prepared by the following reaction steps.
L-valine methyl ester hydrochloride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester thus formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester is treated with tributyltin azide to give valsartan methyl ester, which is then hydrolyzed under alkaline condition to give finally valsartan.
4-[(2′-Cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester may also be prepared by reductive amination of 2′-cyanobiphenyl-4-carbaldehyde with L-valine methyl ester using sodium cyanoborohydride.
The above process requires chromatographic techniques to isolate/purify the intermediates, particularly those that are formed in N-alkylation, N-acylation and tetrazole formation steps.
Since it requires chromatographic separations in many stages, the above process is complicated in operation and large-scale equipment is required, which results in poor productivity. In view of these drawbacks, the above process can hardly be said to be an advantageous one from the industrial production viewpoint.
According to U.S. Pat. No. 5,399,578 and Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 1, pp. 29-34, 1994, valsartan is also prepared by the following reaction steps.
L-valine benzyl ester hydrochloride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester so formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester. N-[2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester is treated with tributyltin azide to give valsartan benzyl ester. Valsartan benzyl ester is subjected to catalytic hydrogenation using for example palladium-charcoal as catalyst to give valsartan.
According to WO 04111018 Valsartan is prepared by the hydrolysis of valsartan benzyl ester with an alkali metal hydroxide, washing with an organic solvent, acidifying with hydrochloric acid and isolating valsartan from the reaction mixture.
WO 2005/021535 provides a method of removing the trityl group from benzyl ester of trityl valsartan by solvolysis in anhydrous alcohol, which is deprived of excess of methyltriphenylether.
According to WO 2005/049586 valsartan is prepared by the reaction of L-valine methylester and 2N-trityl-5-(4′-bromomethylbiphenyl-2-yl)tetrazole followed by acylation with valeryl chloride to give N-pentanoyl-N-[[2′-(2N-trityl-tetrazole-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valinemethylester. On removal of the trityl group under acidic conditions, valsartan methyl ester is obtained. valsartan methyl ester on reaction with metallic and ammonium trialkylsilanolates yields valsartan.
According to WO 2006/058701 A1 valsartan is prepared by the reaction of 5-(4-Bromomethyl)-biphenyl-2-yl)-1-(triphenylmethyl)tetrazole and L-valine methyl ester followed by acylation with valerylchloride and deprotection of the resulting compound to give valsartan. The product obtained by the reaction of 5-(4-Bromomethyl)-biphenyl-2-yl)-1-(triphenylmethyl)tetrazole and L-valine methyl ester is free of di alkylated product.
WO 2005/102987 provides the reaction of 4-Bromobenzylic bromide and hydrochloride methylester of L-valine methylester in an aprotic solvent and organic or an inorganic base to give methylester of N-(4-bromobenzyl)-L-valine which is deprotected to give N-(4-bromobenzyl)-L-valine. This on acylation with valeryl chloride yields N-(4-bromobenzyl)-N-valeryl-L-valine. Valsartan is prepared by the reaction of N-(4-bromobenzyl)-N-valeryl-L-valine and 2-(1H-tetrazole-5-yl)phenylboronic acid in palladiumtetrakistriphenylphosphine.
According to US 2006/0149079 A1 N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methylester is acylated with valerylchloride in the presence of inorganic base to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methylester with valerylchloride, followed by the conversion of cyano to tetrazole and hydrolyzing the tetrazole derivative to obtain valsartan.
According to WO 2006/067216 valsartan is prepared by the condensation of valine derivative with phenylboronic acid derivative to give 4-valinylmethylphenyl boronic acid derivative, which is treated with halophenyl tetrazole in the presence of a metallic base, followed by the deprotection of tetrazole to give valsartan.
According to US 2006/0211866 A1 valsartan is prepared by the condensation of valine moiety and biphenyl derivative in the presence of a phase transfer catalyst in a biphasic solvent system.
According to EP 1714963 4-Bromomethyl-2′-cyanobiphenyl is condensed with L-valinebenzylester tosylate to give (S)-N-[(2′-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester hydrochloride. (S)-N-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester on reaction with valerylchloride yields (S)-N-cyanobiphenyl-4-yl]methyl]-N-valeryl-(L)-valine benzylester further by the reaction of tributyltin chloride and sodiumazide gives benzyl valsartan and debenzylation with Pd/C to give valsartan. Also discloses the process for the recovery of benzyl valsartan substantially free of organo tin impurity.
According to WO 2007/032019 A1 valsartan is prepared by the condensation of 4-halomethyl-2′-cyanobiphenyl with L-valine benzylester to give N-[(2′-cyanobiphenyl-4-yl]methyl]-(L)-valine ester derivative. N-[(2′-cyano biphenyl-4-yl]methyl]-(L)-valine ester derivative is treated with an organic acid to obtain the salt of N-[(2′-cyanobiphenyl-4-yl]methyl]-(L)-valine ester which is substantially free of dimeric impurity, followed by acylation with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl]methyl]-N-valeryl-L-valine ester and further by the conversion to valsartan.
WO 2007/005967 discloses the condensation of p-Bromobenzylbromide with valine methyl ester to give (S)-methyl-2-(4-bromobenzylamino)-3-methyl butanoate which on reaction with valeryl chloride to give (S)-methyl-2-(4-bromobenzyl)pentanamido)-3-methylbutanoate. (S)-methyl-2-(4-bromobenzyl)pentanamido)-3-methylbutanoate is treated with 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid to give (S)-3-methyl-2-{pentanoyl-[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amino}butyric acid methyl ester and base hydrolysis to give trityl valsartan. Triltyl valsartan is treated with an acid to give valsartan.
According to WO 2007/006531 describes the reaction of metal salts of 2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-carboxaldehyde with valine derivative under conditions of reductive amination and acylating the resulting compound with valeryl derivative to give valsartan.
WO2007/045675 discloses the imination of 4-Bromobenzaldehyde with L-valine to give an imine type schiff's base. Reduction of imine group followed by acidification and N-acylation with valerylchloride to give N-(4-bromobenzyl)-N-valeryl-L-valine.
EP 1777224 describes the condensation of p-Bromobenzaldehyde with L-valine followed by reduction with sodium borohydride to give (S)-2-(4-bromobenzyl)amino-3-methylbutyric acid. (S)-2-(4-bromobenzyl)amino-3-methyl butyric acid is treated with valerylchloride to give (S)-2-(4-bromobenzyl)-pentanoyl-amino-3-methyl butyric acid. (S)-2-(4-bromobenzyl)-pentanoyl-amino-3-methyl butyric acid is treated with 2-(2H-tetrazol-5-yl)benzene-boronic acid in tetrahydrofuran, triphenylphosphine and palladiumacetate yield valsartan.
WO 2007/054965 describes the reaction of N-[2′-cyanobiphenyl-4-yl)methyl]-L-valinemethylester oxalate salt and valeryl chloride to give N-[(2-cyanobiphenyl-4-yl)methyl]-N-pentanoyl-L-valine methylester followed by the treatment with tributyltin chloride, sodium azide and triethylamine to give valsartan.
WO2007/057919 discloses the preparation of valsartan by the hydrolysis of valsartan ester derivative in the presence of phase transfer catalyst. Valsartan ester is prepared by the treatment of N-[(2′-cyanobiphenyl-4-yl)methyl]-N-pentanoyl-L-valineester derivative with tributyl tin azide and tetrabutyl ammonium bromide.
WO 2007/071750 describes the reaction of L-valine benzyl ester tosylate and 4-(5,5-dimethyl-[1,3,2]-dioxaborinan-2-yl)benzaldehyde in triethylamine to give benzyl N-[4-(5,5-dimethyl-[1,3,2]-dioxaborinan-2-yl)phenyl-4-yl-methyl]-L-valinate which on acylation and followed by debenzylation to give N-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl-4-yl-methyl]-N-pentanoyl-L-valine. 5-(2-Bromophenyl)-1-triphenylmethyl-1H tetrazole, N-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl-4-yl-methyl]-N-pentanoyl-L-valine in a solution of Pd(Oac)2 and PPh3 in tetrahydrofuran to give valsartan.
According to WO 2008/004110 L-valinemethylester hydrochloride is added to a mixture of 1-triphenylmethyl-5-[4′-(bromomethyl)biphenyl-2-yl]-tetrazole, N,N-dimethylformamide and then treated with oxalic acid to give N-[[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]L-valine methylester oxalate. N-[[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester oxalate is basified and then added valerylchloride to give N-[[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-N-valeryl-L-valine methyl ester. Deprotection of N-[[2′-(1-triphenylmethyl tetrazol-5-yl)biphenyl-4-yl]methyl]-N-valeryl-L-valine methylester using anhydrous acidic conditions to produce valsartan methylester followed by treating with a base to produce valsartan.
WO 2008/007391 describes a process for the preparation of valsartan which involves the conversion of N-[(2′-Cyano[1,1-biphenyl]-4-yl)methyl]-L-valine methylester to N-[[2′-(1H-tetrazol-5yl)[1,1′-biphenyl-4-yl]methyl]-L-valine in the presence of mixture of metal azide and alkyl tin halide followed by the condensation of N-[[2′-(1H-tetrazol-5yl)[1,1-b]phenyl-4-yl]methyl]-L-valine with 5-Phenylthiovaleric acid derivative to give N-(5-(phenylthio)-1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-L-valine and desulfurisation with transition metal halide hydrate to give valsartan.
N-[(2′-cyano[1,1′-biphenyl]-4-yl)methyl]-L-valine benzylester of formula I shown in the specification is the key intermediate in the preparation of valsartan or a pharmaceutical acceptable salt. The intermediate is obtained by the alkylation of L-valine benzyl ester of formula:
with 4-Bromomethyl-2-cyano biphenyl of formula:

The processes describes in the prior art for the preparation of N-[(2′-cyano[1,1′-biphenyl]-4-yl)methyl]-L-valine benzylester results in the formation of an high content of by-product of formula:
as impurity. The formation of this impurity is more pronounced in the scale up batches. The impurity thus obtained is converted further in the following way as shown below during the preparation of valsartan.

Thus, valsartan produced by the prior art contains the impurity of formula:

The impurity thus formed is difficult to remove and it requires repeated purifications to obtain pure valsartan resulting in heavy loss of the yield of valsartan. Therefore it is required to control the formation of corresponding impurity at the source the impurity formation so that the content of the impurity at the source is at a minimum possible level and to isolate the corresponding impurity formed at the source of formation. Even though the patent publication WO 2007/032019 addresses the separation of the impurity, the separation requires the conversion of N-[(2′-cyano[1,1′-biphenyl]-4-yl)methyl]-L-valine benzylester in to the an acid addition salt, and crystallization of the acid addition salt and basifying before proceeding to the preparation of valsartan. Thus, the process involves the additional chemical reaction steps. There still requires a simple but effective process for obtaining valsartan in high purity and high yield.
Thus, there is a need for obtaining valsartan or a pharmaceutically acceptable salt in a pure form and in a better yield.
According to one object of the present invention, there is provided a process for obtaining N-[2′-cyano[1,1′-biphenyl]-4-yl)methyl]-L-valine benzyl ester substantially free of N-bis-[(2′-cyano[1,1′-biphenyl]-4-yl)methyl]-L-valine benzylester.
According to another object of the present invention there is provided free base of N-[(2′-cyano[1,1′-biphenyl]-4-yl)methyl]-L-valine benzylester substantially free of N-bis-[(2′-cyano[1,1′-biphenyl]-4-yl)methyl]-L-valinebenzylester.
N-[(2′-cyano[1,1′-biphenyl]-4-yl)methyl]-L-valine benzylester may be used for preparing valsartan or pharmaceutically acceptable salt thereof in high purity and better yield.